The present invention, in some embodiments thereof, relates to functionalized titanium binding peptides and, more particularly, but not exclusively, to titanium binding peptides which are capable of promoting bone growth and mineralization.
Attempts to use titanium for implant fabrication dates to the late 1930's. It was found that titanium was tolerated in cat femurs, as was stainless steel and vitalium (a CoCrMo alloy). Titanium's lightness and good mechanical and chemical properties are salient features for implant applications. One titanium alloy (Ti6Al4V) is widely used to manufacture implants. The main alloying elements of this alloy are aluminium (5.5-6.5%) and vanadium (3.5-4.5%). Whilst the strength of the titanium alloys varies from lower than to equal to that of stainless steel, when compared by specific strength (strength per density), the titanium alloys outperform any other implant material.
More than 1000 tonnes (2.2 million pounds) of titanium devices of every description and function are implanted in patients worldwide every year, including for bone and joint replacement, dental implants, maxillo and cranio/facial treatments and cardiovascular devices. Light, strong and totally bio-compatible, titanium is one of few materials that naturally match the requirements for implantation in the human body.
The natural selection of titanium for implantation is determined by a combination of most favourable characteristics including immunity to corrosion, bio-compatibility, strength, low modulus and density and the capacity for joining with bone and other tissue—osseointegration. The mechanical and physical properties of titanium alloys combine to provide implants which are highly damage tolerant. The human anatomy naturally limits the shape and allowable volume of implants. The lower modulus of titanium alloys compared to steel is a positive factor in reducing bone resorbtion. Two further parameters define the usefulness of the implantable alloy, the notch sensitivity,—the ratio of tensile strength in the notched vs. un-notched condition, and the resistance to crack propagation, or fracture toughness. Titanium scores well in both cases. Typical NS/TS ratios for titanium and its alloys are 1.4-1.7 (1.1 is a minimum for an acceptable implant material). Fracture toughness of all high strength implantable alloys is above 50 MPam-1/2 with critical crack lengths well above the minimum for detection by standard methods of non-destructive testing.
Titanium (Ti) spontaneously forms an oxide layer up to a thickness of about 2 to 5 nm both in air and in the body, providing corrosion resistance. However, the normal oxide layer of titanium is not sufficiently bioactive to form a direct bond with juxtaposed bone, which may translate into a lack of osseointegration, leading to long-term failure of titanium implants.
In the past, many attempts have been made to improve the surface properties of Ti-based implants; e.g., by modifying Ti topography, chemistry, and surface energy, in order to better integrate into bone. Surface modification techniques include mechanical methods such as sand blasting, chemical methods such as acid etching, and the use of various coatings. A disadvantage of these approaches is that neither the mechanical nor the chemical methods produce highly controllable topological properties, and cell/tissue adherence may be unpredictable or insufficient for practical use. In some cases, the methods may cause formation of surface residuals, which can be interfere with osteoblast (bone forming cell) adherence and function.
Despite progress in modifying metal surfaces to improve tissue and cell adhesion properties, adequate in vivo osseointegration on implant prostheses remains a challenge. Substrates that promote significant bone-tissue interactions with biomaterial surfaces over a period of time would be highly desirable. In order to ensure effective tissue adhesion, and thus clinical success of orthopaedic/dental implants, it is important to develop stable, biocompatible surfaces that enhance osteoblast functions for new bone formation. Additionally, the increasing importance of antimicrobial and other bioactive agents for in vivo implants requires improved materials and more effective means of releasing drugs at selected sites in the body.
Gertler et al [Langmuir, 2010) teach titanium surfaces attached to peptides.
U.S. Patent Application No. 20100015197 teaches amphiphilic peptides and peptide matrices thereof useful in vitro and in situ biomineralization and inducing bone repair.
Meyers et al [Advanced Materials, 2007, 19, 2492-2498] teaches a 20-30 mer peptide that comprises a titanium binding domain and a domain that binds to endothelial cells. The peptides were identified using a genetically engineered peptide library. The drawback of this approach lies in the panning procedure which uses limited adsorption and desorption conditions. The panning enriches the electrostatically physiosorbed peptides, while leaving strongly bound ones unrevealed.